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Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration

Lookup NU author(s): Dr Ioana Cosgarea, Dr Ashleigh McConnell, Dr Tom Ewen, Dr Diana Tang, Dr David Hill, Maria Anagnostou, Martina Elias, Dr Robert Ellis, Alex Murray, Alison Greenwood, Dr Jane Armstrong, Professor Penny Lovat

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2021 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of DermatologistsBackground: For patients with early American Joint Committee on Cancer (AJCC)-stage melanoma the combined loss of the autophagy regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoral epidermis is associated with a significantly increased risk of metastasis. Objectives: The aim of the present study was to evaluate the potential contribution of melanoma paracrine transforming growth factor (TGF)-β signalling to the loss of AMBRA1 in the epidermis overlying the primary tumour and disruption of epidermal integrity. Methods: Immunohistochemistry was used to analyse AMBRA1 and TGF-β2 in a cohort of 109 AJCC all-stage melanomas, and TGF-β2 and claudin-1 in a cohort of 30 or 42 AJCC stage I melanomas, respectively, with known AMBRA1 and loricrin (AMLo) expression. Evidence of pre-ulceration was analysed in a cohort of 42 melanomas, with TGF-β2 signalling evaluated in primary keratinocytes. Results: Increased tumoral TGF-β2 was significantly associated with loss of peritumoral AMBRA1 (P < 0·05), ulceration (P < 0·001), AMLo high-risk status (P < 0·05) and metastasis (P < 0·01). TGF-β2 treatment of keratinocytes resulted in downregulation of AMBRA1, loricrin and claudin-1, while knockdown of AMBRA1 was associated with decreased expression of claudin-1 and increased proliferation of keratinocytes (P < 0·05). Importantly, we show loss of AMBRA1 in the peritumoral epidermis was associated with decreased claudin-1 expression (P < 0·05), parakeratosis (P < 0·01) and cleft formation in the dermoepidermal junction (P < 0·05). Conclusions: Collectively, these data suggest a paracrine mechanism whereby TGF-β2 causes loss of AMBRA1 overlying high-risk AJCC early-stage melanomas and reduced epidermal integrity, thereby facilitating erosion of the epidermis and tumour ulceration.


Publication metadata

Author(s): Cosgarea I, McConnell AT, Ewen T, Tang D, Hill DS, Anagnostou M, Elias M, Ellis RA, Murray A, Spender LC, Giglio P, Gagliardi M, Greenwood A, Piacentini M, Inman GJ, Fimia GM, Corazzari M, Armstrong JL, Lovat PE

Publication type: Article

Publication status: Published

Journal: British Journal of Dermatology

Year: 2021

Pages: epub ahead of print

Online publication date: 13/11/2021

Acceptance date: 29/10/2021

Date deposited: 26/01/2022

ISSN (print): 0007-0963

ISSN (electronic): 1365-2133

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.1111/bjd.20889

DOI: 10.1111/bjd.20889

PubMed id: 34773645


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Funding

Funder referenceFunder name
British Skin Foundation (A.T.M., D.T., R.A.E., J.L.A. and P.E.L.),
Assocaizione Italiana per la Ricerca sul Cancro (AIRC, MFAG-11743 to M.C.),
CRUK (G.J.I.) and by a scholarship to I.C. from the Deutsche Forschungsgemeinschaft (DFG, CO 1931/1-1).
Melanoma Focus (I.C., A.T.M., D.S.H., M.A., M.E., R.A.E., A.G. and J.L.A., by a project grant to R.A.E. and P.E.L.),
IG2015 no. 17404 to G.M.F. and IG2018 no. 21880 to M.P., and Ricerca Corrente (Italian Ministry of Health) to G.M.F. and M.P.
Newcastle Health Care Charity (A.T.M., D.S.H., M.A., R.A.E. and P.E.L.)
North East Skin Research Fund (T.E., M.E., R.A.E. and P.E.L.)
University of Sunderland Beacon Fund (J.L.A.),
Worldwide Cancer Research [L.C.S. and G.J.I., by a project grant (11-078) to G.J.I.]

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